Intramolecular Formation of Zwitterionic Intermediates in 1,3-Diaza-Claisen Rearrangements

Article abstract of DOI:10.1021/acs.orglett.7b01746

Isothioureas tethered to bridged-bicyclic tertiary allylic amines can be converted to carbodiimides through reaction with Hg(II) salts. Intramolecular cyclization of the tethered tertiary allylic amines to the carbodiimides afford zwitterionic intermediat

Full text of DOI:10.1021/acs.orglett.7b01746

Letter
pubs.acs.org/OrgLett
Intramolecular Formation of Zwitterionic Intermediates in 1,3-Diaza-
Claisen Rearrangements
Joel D. Walker, Rebecca Watson, Stevenson Flemer, Yanbo Yang, and Jose S. Madalengoitia*
́
Department of Chemistry, University of Vermont, Burlington, Vermont 05405, United States
S
* Supporting Information
ABSTRACT: Isothioureas tethered to bridged-bicyclic tertiary allylic amines can be converted to carbodiimides through
reaction with Hg(II) salts. Intramolecular cyclization of the tethered tertiary allylic amines to the carbodiimides afford
zwitterionic intermediates that undergo 1,3-diaza-Claisen rearrangements, affording highly substituted tricyclic guanidines.
e have previously described methodology for the
synthesis of highly substituted guanidines through the
The new proposed rearrangement brought up an interesting
electronic/regioisomeric issue. Specifically, in the intermolecular
reaction of thiourea 6 with aza-norbornene 5, the only
regioisomer isolated is isomer 7, in which the electron
withdrawing Ts-group results on the imine nitrogen of the
guanidine (Figure 2).1,2 We have never observed the other
W
in situ generation of an electron-deficient carbodiimide from an
isothiourea, thiourea, or urea followed by the addition of a tertiary
allylic amine to the carbodiimide affording a zwitterionic
intermediate that in turn undergoes a 1,3-diaza-Claisen
rearrangement.1−5 In previously reported examples of the 1,3-
diaza-Claisen rearrangement, the overall process involved the
intermolecular reaction of the tertiary allylic amine with the
carbodiimide. In this work, we investigate systems in which the
carbodiimide and tertiary allylic amine are tethered and thus form
the zwitterionic intermediate through the intramolecular reaction
of these species. Originally, we envisioned the conversion of
thioureas 1 into carbodiimides 2 (Figure 1). Attack of the tertiary
Figure 2. Reaction of aza-norbornene 5 and thiourea 6 affords only
regioisomer 7 indicating a higher energy of activation for transition state
10.
Figure 1. Proposed transformation of thioureas 1 into carbodiimides 2
followed by cyclization to zwitterionic intermediates 3 and rearrange-
ment to guanidines 4.
possible regioisomer 8. This result suggests that isomer 7 forms
faster than isomer 8 and that the energy of activation for the
formation of 8 is higher than for the formation of 7. In the
proposed intramolecular rearrangement, by necessity, the
electron-withdrawing group is constrained by the system to not
end up on the imine nitrogen. It was thus unknown at the start of
allylic amine on the carbodiimide would result in intramolecular
formation of zwitterionic intermediate 3 that would in turn
rearrange into the tricyclic guanidine 4. The advantage of the
tethered tertiary allylic amine and carbodiimide lies in the
formation of an additional ring and thus in an increase in
molecular complexity as part of the overall process.
Received: June 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01746
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Letter
the project whether the intramolecular rearrangement would be
feasible due to the less than ideal electronics.
Our initial studies focused on the synthesis of the aza-
norbornene tethered through a three-carbon chain to the
thiourea (Figure 3). LAH reduction of the commercially available
concentration of amine 15. Indeed, this experimental setup
resulted in the isolation of thiourea 18 in 52% yield. However,
products 16 and 17 were still formed in 18% combined yield.
With thiourea 18 in hand, we subjected 18 to carbodiimide
formation conditions (EDCI, CHCl3), but thiourea 18 did not
undergo any reaction. This was surprising to us since the
transformation of thioureas to carbodiimides by EDCI and the
subsequent trapping of carbodiimides by amines is, from our
experience, a fast process (usually complete in less than 15 min).7
The reaction was also attempted under forcing conditions
(heating at reflux), but this resulted in decomposition. Attempted
formation of the carbodiimide with the Mukayiama salt at room
temperature and at elevated temperatures also failed to yield any
rearrangement product (data not shown). We have also
investigated the reaction of amine 15 with the more reactive
TsNCS using the syringe pump addition of TsNCS to 2 equiv of
amine 15, but with this more reactive isocyanate, the
corresponding thiourea was only obtained in 24% yield and
attempted rearrangements of this thiourea also failed (data not
shown). All these combined results suggested that perhaps we
needed a different, less reactive, carbon(IV) source than an
isocyanate and a different carbodiimide precursor than a thiourea.
Aryl sulfonyl S,S-dimethyl carbodithioimidates seemed ideal
reagents for our purposes as they are far less reactive than
isothiocyanates and react with amines to give isothioureas that
can be readily converted to carbodiimides with thiophilic
metals.8−11 Indeed, the amine 15 reacted with carbodithioimi-
dates 19−21 to give the corresponding isothioureas 22−24
bearing a range of electron withdrawing groups to allow
determination of the electron-withdrawing group effect on the
rearrangement.12,13
With the synthesis of the analogues with a three-carbon-tether
between aza-norbornene and the isothiourea complete, attention
was refocused on completing the synthesis of the two- and four-
carbon-tethered analogues. Reaction of glycine methyl ester
hydrochloride with aqueous formaldehyde and cyclopentadiene
afforded aza-norbornene 25 in 83% yield through the hetero-
Diels−Alder reaction (Figure 4).14 Ammonolysis of the ester in a
saturated methanol solution afforded the amide 26 in 89% yield.
Finally, LAH reduction of the amide in THF at reflux followed by
reaction of the subsequent amine 27 with carbodithioimidate 19
afforded the isothiourea 28 in 55% yield for both steps. It is worth
noting that we found the amine 27 volatile and was best used
Figure 3. Synthesis of amine 15 from lactam 12. Reaction of a 1:1
stoichiometry of 15with EtO2NCS did notafford the desired thiourea 18
but rather the isomers 16 and 17. Reaction of a 2:1 stoichiometry of 15 to
EtO2CNCS afforded the thiourea 18 in 52% yield. Attempted
carbodiimide formation from 18 with EDCI did not afford any
rearrangement product. However, isothioureas 22−24 could be
synthesized from the reaction of 15 with carbodithioimidates 19−21
as alternative carbodiimide precursors to the corresponding thioureas.
lactam 12 in THF at reflux followed by isolation of the amine as
the hydrochloride salt afforded the salt 13 in 75% yield.6 In situ
generation of the free base of the hydrochloride salt 13 with
KHCO3 in DMF followed by conjugate addition to acrylonitrile
afforded the nitrile 14 in 72% yield with the requisite three-
carbon chain appropriately functionalized for conversion to the
urea. Reduction of the nitrile 14 with LAH in Et2O at reflux
afforded the primary amine 15 in 52% yield. However, the
attempted reaction of amine 15 with ethoxycarbonyl isothiocya-
nate did not afford any of the desired thiourea 18. Instead, the
regioisomeric products 16 and 17 in which isothiocyanate had
reacted with aza-norbornene at both the primary and tertiary
amine were isolated as a 4:1 mixture, respectively, in 68% yield.
The isolation of products 16 and 17, resulting from the
reaction of amine 15 with 2 equiv of isothiocyanate, prompted us
to investigate an alternative strategy. The reaction was run by
syringe pump addition of ethoxycarbonyl isothiocyanate to a
solution of 2 equiv of amine in CH2Cl2 at 0 °C. The idea behind
this strategy was that under these reaction conditions, as thiourea
18 begins to form, the slowly added isocyanate would react with
amine 15 preferentially over the thiourea 18 due to the higher
Figure 4. Hetero-Diels−Alder of cyclopentadiene with in situ generated
iminium ion from formaldehyde and glycine methyl ester hydrochloride
affords the aza-norbornene 25. Ammonolysis of 25 affords the amide 26
that is reduced to the amine 27 with LAH. Reaction of amine 27 with 19
affords the isothiourea 28.
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immediately after the Fieser workup without removing the THF
solvent under vacuum.
The synthesis of the four-carbon-tethered analogue was
completed by an analogous strategy used above (Figure 5).
LAH in THF according the procedure of Malpass gave the amine
32 in 70% yield.17 Conjugate addition of the amine 32 to
acrylamide was accomplished by heating in MeOH at reflux for 3
h to afford the isoquinuclidene 33 with the three-carbon tether in
86% yield. LAH reduction of the amide and subsequent reaction
of the corresponding amine with carbodithioimidate 19 afforded
the isothiourea 35 in 61% yield for both steps.
With the synthesis of the series of representative isothioureas
complete, effort was focused on the critical one pot carbodiimide
formation, cyclization to form the zwitterionic intermediate,
followed by rearrangement to afford the corresponding
guanidines. Reaction of isothiourea 28 with HgCl2 in the
presence of Et3N in DMF gratifyingly afforded the tricyclic
guanidine 36 in 82% yield (Figure 7). We had originally thought
Figure 5. Hetero-Diels−Alder reaction of cylcopentadiene with in situ
generated iminium ion derived from formaldehyde and methyl 4-amino
butyrate hydrochloride affords aza-norbornene 29. Ammonolysis of
ester affords amide 30. LAH reduction of amide and reaction of amine
with Pbf-carbonochloridoimidothioate affords isothiourea 31.
Hetero-Diels−Alder reaction of methyl 4-aminobutyrate hydro-
chloride with aqueous formaldehyde and cyclopentadiene
afforded the aza-norbornene 29 with the requisite four-carbon
tether in 51% yield. Ammonolysis of the ester smoothly gave the
amide 30 in 99% yield. LAH reduction of the amide afforded the
amine that was carried on to the following reaction without
purification. Curiously, while we had had success in the reaction
of primary amines with S,S-dimethyl carbodithioimidate 19 to
make isothioureas, the amine derived from the reduction of
amide 30 failed to afford any of the corresponding isothiourea.
We investigated several reaction conditions, including different
solvents, elevated temperatures as well as neat conditions without
any success. As such, we explored the reaction of the amine with
methyl tosylcarbonochloridoimidothioate which did afford the
corresponding isothiourea 31 in 45% yield from the amide
30.15,16 While in the series of homologues 22 and 28 we have
been working with Pbf-protected isothioureas, the tosylisothiour-
ea 31 breaks this trend. The synthesis of methyl Pbf-
carbonochloridoimidothioate was attempted by heating 29
with sulfuryl dichloride in CH2Cl2, but instead of the desired
product, the product obtained was consistent with free-radical
chlorination of a benzylic position of the Pbf group. We expect
the Pbf and Ts to behave similarly, despite the many more
electron-releasing groups on the aromatic group.
Figure 7. Activation, cyclization, and rearrangement of isothioureas.
that this rearrangement would be challenging because examina-
tion of models suggested that for a suprafacial−suprafacial
rearrangement, the orbital alignment was not optimal for such a
rigid framework (Figure 8). This suboptimal orbital arrangement,
The final rearrangement precursor was synthesized as
described in Figure 6. Reduction of the known lactam 32 with
Figure 8. Orbital overlap necessary for rearrangement.
however, may be compensated for by the coupling of bond
breakage to the release ring strain in the transition state. It is also
noteworthy that the rearrangement proceeded in spite of the less
than ideal electronics (noted in Figure 2) in which the electron-
withdrawing group cannot end up on the imine nitrogen. This
result suggests that while transition state 11 may have a higher
energy of activation than transition state 10, the energy of
activation for transition state 11 is still lower than for a transition
state not possessing an electron-withdrawing group.
Reaction of isothiourea 22 (possessing a three-carbon tether)
with HgCl2 and Et3N in DMF afforded the tricyclic guanidine 37
in 57% yield. We have additionally investigated the desulfuriza-
Figure 6. LAH reduction of lactam 32 affords amine 33. Conjugate
addition of 33 to acrylamide gives amide 34. LAH reduction of the amide
and subsequent reaction of the amine with 19 yields isothiourea 35.
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tion of isothiourea 22 with AgCl as a greener alternative to HgCl2
and have found that the guanidine 37 is obtained in comparable
yield (data not shown). Interestingly, it appears that an aryl
sulfonyl group is close to an optimal electron-withdrawing group
for these rearrangements with the mismatched electronics since
the attempted rearrangement of isothiourea 23 with a more
powerfully electron-withdrawing trifluoromethylsufonyl group
afforded a complex mixture, and the attempted reaction of
isothiourea 24 with the less powerfully electron-withdrawing
benzoyl group also ended in decomposition. The reaction of the
four-carbon tethered isothiourea 31 with HgCl2 and Et3N in
CH2Cl2 smoothly afforded the tricyclic guanidine 38 in 60%
yield. Finally, the reaction of isothiourea 35 with Hg(II) in DMF
gave the guanidine 39 in 68% yield. This last result is quite
significant as in the intermolecular reaction of N-benzyl
isoquinuclidene with N-benzyl-N′-tosyl thiourea under no
conditions studied was the rearrangement product observed.2
To undergo the 1,3-diaza-Claisen rearrangement, N-benzyliso-
quinuclidene required N-benzyl-N′-Tf thiourea and heating at 60
°C overnight (Figure 9).2 In contrast, isothiourea 35 converted to
sin.20 It is thus possible that the application of the strategy of
intramolecular formation of zwitterionic intermediate followed
by 1,3-diaza-Claisen rearrangement on the appropriate substrates
may be applicable the synthesis of these natural products.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01746.
1H NMR spectra for compounds 16, 18, and 23. 1H NMR
and 13C NMR spectra for compounds 14, 15, 19, 22, 24,
26, 28−30, 35−39 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jmadalen@uvm.edu.
ORCID
Jose S. Madalengoitia: 0000-0002-9999-1216
́
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Funding for this work was provided by Grant No. CHE 1111694
from the NSF.
■
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Org. Lett. XXXX, XXX, XXX−XXX